Document Detail

Hypoxia potentiates microRNA-mediated gene silencing through posttranslational modification of Argonaute2.
MedLine Citation:
PMID:  21969601     Owner:  NLM     Status:  MEDLINE    
Hypoxia contributes to the pathogenesis of various human diseases, including pulmonary artery hypertension (PAH), stroke, myocardial or cerebral infarction, and cancer. For example, acute hypoxia causes selective pulmonary artery (PA) constriction and elevation of pulmonary artery pressure. Chronic hypoxia induces structural and functional changes to the pulmonary vasculature, which resembles the phenotype of human PAH and is commonly used as an animal model of this disease. The mechanisms that lead to hypoxia-induced phenotypic changes have not been fully elucidated. Here, we show that hypoxia increases type I collagen prolyl-4-hydroxylase [C-P4H(I)], which leads to prolyl-hydroxylation and accumulation of Argonaute2 (Ago2), a critical component of the RNA-induced silencing complex (RISC). Hydroxylation of Ago2 is required for the association of Ago2 with heat shock protein 90 (Hsp90), which is necessary for the loading of microRNAs (miRNAs) into the RISC, and translocation to stress granules (SGs). We demonstrate that hydroxylation of Ago2 increases the level of miRNAs and increases the endonuclease activity of Ago2. In summary, this study identifies hypoxia as a mediator of the miRNA-dependent gene silencing pathway through posttranslational modification of Ago2, which might be responsible for cell survival or pathological responses under low oxygen stress.
Connie Wu; Jessica So; Brandi N Davis-Dusenbery; Hank H Qi; Donald B Bloch; Yang Shi; Giorgio Lagna; Akiko Hata
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-03
Journal Detail:
Title:  Molecular and cellular biology     Volume:  31     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-09     Completed Date:  2011-12-30     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4760-74     Citation Subset:  IM    
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MeSH Terms
Argonaute Proteins / genetics,  metabolism*
Cell Hypoxia / genetics
Cells, Cultured
Cytoplasmic Granules / metabolism
Eukaryotic Initiation Factors / genetics,  metabolism
Gene Expression
Gene Expression Regulation
Genes, Reporter
Green Fluorescent Proteins / biosynthesis,  genetics
HSP90 Heat-Shock Proteins / metabolism
Lung / cytology,  metabolism
MicroRNAs / genetics,  metabolism*
Muscle, Smooth, Vascular / cytology
Myocytes, Smooth Muscle / metabolism
Primary Cell Culture
Procollagen-Proline Dioxygenase / genetics,  metabolism
Protein Processing, Post-Translational*
Protein Transport
Pulmonary Artery / cytology
RNA Interference*
Ribonuclease III / metabolism
Grant Support
Reg. No./Substance:
0/Argonaute Proteins; 0/EIF2C1 protein, human; 0/EIF2C2 protein, human; 0/EIF2C3 protein, human; 0/EIF2C4 protein, human; 0/Eukaryotic Initiation Factors; 0/HSP90 Heat-Shock Proteins; 0/MicroRNAs; 147336-22-9/Green Fluorescent Proteins; EC Dioxygenase; EC protein, human; EC III

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